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1078-0432.CCR-15-0737.Full-Text.Pdf Author Manuscript Published OnlineFirst on September 18, 2015; DOI: 10.1158/1078-0432.CCR-15-0737 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-coding small RNAs as biomarkers for high stage and locally metastatic colorectal cancer Distinct profiles for mitochondrial t-RNAs and small nucleolar RNAs in locally invasive and metastatic colorectal cancer. Lai Xu1, Joseph Ziegelbauer2, Rong Wang1, Wells W. Wu3, Rong-Fong Shen3, Hartmut Juhl4, Yaqin Zhang1, Amy Rosenberg1* (corresponding author). 1OBP/DBRR-III, CDER, FDA, Silver Spring, Maryland, 2 HIV/AIDS Malignancy Branch, NCI, Bethesda, Maryland, 3 Facility for Biotechnology Resources, CBER, FDA, Silver Spring, Maryland, 4 Indivumed GMBH. Hamburg, Germany. Running Title: Small RNAs as novel biomarkers in colorectal cancer Keywords: MT-tRNAs, snoRNAs, microRNAs, mRNAs and tumor biomarkers *Correspondence should be addressed to Amy Rosenberg Bldg 71, Rm 2238 10903 New Hampshire Ave Silver Spring, MD 20903 ([email protected]) Disclosure of Potential Conflicts of Interest There are no current financial considerations to disclose. 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2015; DOI: 10.1158/1078-0432.CCR-15-0737 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-coding small RNAs as biomarkers for high stage and locally metastatic colorectal cancer Statement of translational relevance: The precise molecular profiling of colorectal cancer (CRC) should facilitate development of better staging systems as well as identify targets for development of novel treatments. Our study focused principally on non-coding RNAs in the characterization of tumors at high stage and with metastases. We identified mitochondrial transfer RNAs (MT-tRNAs) as the top upregulated small RNAs (sRNAs) in high stage CRC and in CRC with defined metastases. We also found that small nucleolar RNAs (snoRNAs) downregulated in Prader-Willi syndrome (PWS), a metabolic disorder characterized by obesity (energy storage), were commonly downregulated in CRC. These findings indicate that a hallmark of tumor aggressiveness/progression pertains to energy storage and endowment of mitochondria with enzymes critical for oxidative phosphorylation, despite a shift to glycolytic metabolism in such tumors. 2 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2015; DOI: 10.1158/1078-0432.CCR-15-0737 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-coding small RNAs as biomarkers for high stage and locally metastatic colorectal cancer Abstract: Purpose: To gain insight into factors involved in tumor progression and metastasis, we examined the role of non-coding RNAs (ncRNAs) in the biological characteristics of colorectal carcinoma (CRC), in paired samples of tumor together with normal mucosa from the same CRC patient. The tumor and healthy tissues samples were collected and stored under stringent conditions, thereby minimizing warm ischemic time. Experimental Design: We focused particularly on distinctions among high stage tumors and tumors with known metastases, performing RNA-Seq analysis which quantifies transcript abundance and identifies novel transcripts. Results: In comparing 35 CRCs, including 9 metastatic tumors (metastases to lymph nodes and lymphatic vessels (LN/LV)), to their matched healthy control mucosa, we found a distinct signature of MT-tRNAs and snoRNAs for metastatic and high stage CRC. We also found the following: 1) MT-TF (phenylalanine) and snord12B expression correlated with a substantial number of miRNAs and mRNAs in 14 CRCs examined; 2) a miRNA signature of oxidative stress, hypoxia and a shift to glycolytic metabolism in 14 CRCs, regardless of grade and stage, and 3) heterogeneous MT-tRNA/snoRNA fingerprints for 35 pairs. Conclusions: These findings could potentially assist in more accurate and predictive staging of CRC including identification of those CRC likely to metastasize. 3 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2015; DOI: 10.1158/1078-0432.CCR-15-0737 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-coding small RNAs as biomarkers for high stage and locally metastatic colorectal cancer Introduction CRC is the third most common cancer and also the third leading cause of cancer-related deaths in the United States (1). The prognosis in advanced cases is poor with more than one-third of the patients dying from progressive disease within 5 years (2). However, simultaneous evaluation of sRNA, miRNA and mRNA in matched pairs of CRC by RNA-Seq, a technology for high throughput sequencing of the whole transcriptome with some advantages over microarrays, has not been reported. miRNAs are ncRNA molecules with 18-25 nucleotides (nts) in length and are known to repress mRNAs by inhibiting translation and stimulating mRNA degradation (3). Approximately 270 of such miRNAs have been shown to be dysregulated in CRC (3-5) by real-time PCR and microarray. sRNAs are approximately 60-300 nts in length which include transfer RNAs (tRNAs) and snoRNAs. MT-tRNAs, approximately 70-80 nts long, are structurally distinct from nuclear-encoded tRNAs by having one less loop than the nuclear canonical cloverleaf structure due to genome economization (6). Twenty-two MT-tRNAs and 2 ribosomal RNAs (rRNAs) are required for the synthesis of 13 out of the 84 essential protein subunits of NADH dehydrogenase, cytochrome reductase, cytochrome oxidase and ATP synthase which are essential for ATP production through oxidative phosphorylation in the mitochondria (7). Upregulated expression of such MT- tRNAs has been found in breast cancer (8). snoRNAs play a crucial role in ribosome biogenesis through methylation and pseudouridylation of rRNAs (9). A linkage between snoRNAs and carcinogenesis has been established for non-small-cell lung cancer (NSCLC) (10). mRNAs are RNA templates for protein synthesis and thus far, more than 4 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2015; DOI: 10.1158/1078-0432.CCR-15-0737 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-coding small RNAs as biomarkers for high stage and locally metastatic colorectal cancer a dozen mRNAs have been identified as biomarkers for staging and prognosis of CRC (11). Our study sought to investigate, using stringently collected and preserved tissue samples (12) and RNA-Seq analysis, whether expression of unique sRNA species correlated with and potentially contributed to the aggressive biological behavior of advanced stage colorectal cancers and cancers with known metastasis, as compared to lower grade tumors and healthy tissues. Materials and Methods Cohort Thirty-five paired-tissues of pretreatment CRC were collected by Indivumed GmbH (Germany). Histologically, tumor content is 50-70% in tumors and 0% in normal tissues. Normal tissues were 5 cm away from tumors. Ischemia time to freeze was 6-11 minutes. The normal mucosa was collected in a distal part of the bowel close to the resection margins. Clinical and histopathological characteristics of the patients are summarized in table S1. Small RNA and miRNA sequencing All 35 pairs were sequenced at small RNA level and first 15 pairs were also sequenced at miRNA level. The RNA quality was assessed using the Agilent 2100 Bioanalyzer. Samples with a RNA Integrity Number (RIN) of 7 or higher were processed to generate libraries for small RNA sequencing following the Illumina®TruSeq™ Small RNA 5 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 18, 2015; DOI: 10.1158/1078-0432.CCR-15-0737 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-coding small RNAs as biomarkers for high stage and locally metastatic colorectal cancer Sample Preparation protocols. In brief, 3’ and 5’ RNA adapters, specifically modified to target the 3’ hydroxyl group and 5’ phosphate group of most small RNA molecules, were ligated to the ends of sRNAs present in 1 µg of high quality total RNA. Reverse transcription was performed to generate the first-strand cDNAs followed by synthesis of the second-strand cDNAs. The small RNA libraries were loaded onto a 4% agarose gel after 11-cycle PCR amplification. DNA fragments of 145 to 160 bp containing miRNA inserts were excised from the gel and purified for micro RNA sequencing (miRNA-Seq), while those of 160 - 400 base pair (bp) containing longer inserts were similarly purified for small RNA (including MT-tRNAs and snoRNAs) sequencing (sRNA-Seq). The yield of small RNA library was quantified on Agilent 2100 Bioanalyzer. Twelve to twenty- four small RNA libraries were pooled, denatured and loaded onto one lane of a flow cell for cluster generation using the Illumina cBot. The flow cell was loaded onto Illumina HiSeq 2500 sequencer
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